The gastrointestinal tract is one of the critical target organs afflicted by radiation injury. Abdominal irradiation causes an array of pathology which has been divided into 1) the prodromal phase, 2) acute radiation sickness, and 3) the late effects of radiation. Nausea, vomiting, abdominal cramping and diarrhea, often are the first manifestations of radiation toxicity. These effects are mediated by neural changes and associated with altered motility in the small and large intestine. Studies from our lab have provided evidence for dramatic changes in small and large intestinal motility with direct symptomatic relevance. Secretory diarrhea, a significant contribution to early radiation morbidity and mortality, reflects transfer of intravascular fluids to the intestinal lumen through the epithelium. Our studies of the intestinal microvasculature provide a novel potential method for the prediction and modification of radiation diarrheal illness. New evidence from our lab suggests that the late damaging effects of radiation in the gastrointestinal tract are mediated by both neural and microvascular changes. This grant application proposes to define gastrointestinal effects following both low and high dose rate radiation exposure in two animal models (rat and the dog), as well as developing mitigation strategies to ameliorate damage. In addition, we will explore ACE inhibition, NMDA receptor inhibition and SOD mimetics as a mitigating agents. Contractile recordings will be made from a canine and a rodent model and will be correlated with immunohistochemical studies of the myenteric plexus as well as microvascular studies. Product development and the accumulation of pre-clinical safety data to facilitate submission to the FDA is a priority of this grant application with our ultimate aim to improve human tolerance to radiation exposure. In summary, experimental studies suggest radiation-induced injury to the gastrointestinal tract can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.